本文關(guān)鍵詞：膽汁酸升高的慢性乙型肝炎患者T細(xì)胞免疫衰老及肝細(xì)胞癌風(fēng)險(xiǎn)升高　出處：《第三軍醫(yī)大學(xué)》2016年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： T細(xì)胞免疫衰老 慢性乙型肝炎 端粒 膽汁酸 肝細(xì)胞癌

【摘要】：隨著年齡的增加,天然免疫與獲得性免疫系統(tǒng)功能進(jìn)行性的退化,最終導(dǎo)致免疫力的降低,這個(gè)現(xiàn)象通常被稱為免疫衰老。免疫衰老通常被認(rèn)為與老年人對(duì)疫苗免疫反應(yīng)減低、易于遭受病毒或細(xì)菌感染、易于發(fā)生癌癥相關(guān)。作為獲得性免疫系統(tǒng)的主要組成,免疫衰老過程中T細(xì)胞的功能退化有著最多的關(guān)注。T細(xì)胞免疫衰老通常表型為T細(xì)胞免疫系統(tǒng)多個(gè)層面上的退行性變化,其中包括:naive T細(xì)胞數(shù)量下降,TCR(T-cell Receptor,T細(xì)胞受體)repertoire多樣性降低,T細(xì)胞端�？s短,memory T細(xì)胞功能下降等。目前研究結(jié)果表明慢性病原體感染對(duì)于機(jī)體免疫系統(tǒng)有著負(fù)面的影響。在本研究中,我們分析了是否CHB(Chronic Hepatitis B,慢性乙型肝炎)患者其T細(xì)胞免疫系統(tǒng)受損,同時(shí)我們也分析了是否CHB患者T細(xì)胞免疫系統(tǒng)受損與其發(fā)生HCC(Hepatocellular Carcinoma,肝細(xì)胞癌)相關(guān)。我們比較了24例CHB患者和15例健康人其naive T細(xì)胞庫的TCR repertoire。與以前研究報(bào)道結(jié)果一致,健康人40歲以前其naive T細(xì)胞庫的TCR repertoire多樣性沒有明顯降低保持在高水平。與健康人不同,CHB患者40歲以前其naive T細(xì)胞庫的TCR repertoire多樣性隨著年齡的增加顯著降低�？紤]到這24例CHB患者都是通過垂直傳播感染的HBV(Hepatitis B Virus,乙型肝炎病毒),我們認(rèn)為其naive T細(xì)胞庫的TCR repertoire多樣性的降低是由于HBV病毒與T細(xì)胞免疫系統(tǒng)長期作用的結(jié)果而不是由年齡增加造成的。和健康人naive T細(xì)胞庫一樣,沒有表達(dá)特定TCR克隆型的T細(xì)胞克隆在naive T細(xì)胞庫中占據(jù)主導(dǎo)地位,這表明CHB患者其naive T細(xì)胞庫的TCR repertoire多樣性的降低不是由某些特定TCR克隆型的T細(xì)胞克隆優(yōu)勢(shì)性的擴(kuò)增導(dǎo)致,而很可能反映了CHB患者其naive T細(xì)胞庫T細(xì)胞克隆均勻性的丟失。我們這部分研究的發(fā)現(xiàn)表明慢性CHB感染能夠加速CHB患者的T細(xì)胞免疫衰老。Naive T細(xì)胞庫的TCR repertoire多樣性的降低意味著CHB患者外周T細(xì)胞庫的維持失衡。成年人外周T細(xì)胞庫的維持主要通過T細(xì)胞的緩慢增殖來實(shí)現(xiàn)。首先,我們分析了146例CHB患者及53例健康人外周T細(xì)胞的增殖情況。與健康人相比,CHB患者外周t細(xì)胞增殖水平顯著升高。部分chb患者外周t細(xì)胞的增殖水平升高到了hiv-1(humanimmunodeficiencyvirustype1,人免疫缺陷病毒1型)感染的水平。chb患者血清tba(totalbildacid,總膽汁酸)水平與其外周t細(xì)胞增殖水平升高顯著相關(guān),這主要體現(xiàn)在:從定性的角度分析,血清tba升高的chb患者其所有t細(xì)胞亞群(包括naivet細(xì)胞和memoryt細(xì)胞)的增殖頻率相對(duì)于血清tba正常的chb患者及健康人都顯著升高;從定量的角度分析,血清tba升高的chb患者其外周t細(xì)胞的增殖頻率與其血清tba顯著正相關(guān)。我們也分析了chb患者其外周t細(xì)胞增殖水平升高與其它c(diǎn)hb相關(guān)的臨床指標(biāo)的相關(guān)性,沒有發(fā)現(xiàn)類似的顯著相關(guān)性。隨后,我們分析了11例血清tba持續(xù)升高的chb患者兩個(gè)不同時(shí)間點(diǎn)的t細(xì)胞增殖水平,發(fā)現(xiàn)其t細(xì)胞在前后兩個(gè)時(shí)間點(diǎn)都保持高水平增殖。這表明對(duì)于血清tba持續(xù)升高的chb患者,其外周t細(xì)胞很可能一直保持在過度增殖狀態(tài)。進(jìn)一步,我們分析了12例血清tba升高的chb患者其外周t細(xì)胞的活化情況,同時(shí)比較了這12例chb患者與3例健康人外周增殖的t細(xì)胞與靜息的t細(xì)胞其tcrvβ家族的分布。血清tba升高的chb患者其增殖的t細(xì)胞上調(diào)cd38表達(dá),顯示其免疫活化。盡管增殖水平差異巨大,血清tba升高的chb患者與健康人其增殖的t細(xì)胞與靜息的t細(xì)胞的tcrvβ家族的分布都高度類似。這表明抗原非特異性的旁路活化(by-standeractivation)機(jī)制主導(dǎo)了血清tba升高的chb患者其外周t細(xì)胞增殖水平的升高。最后,我們分析了5例健康人、21例有4年以上跟蹤的chb患者、4例hbv相關(guān)的hcc患者其naivet細(xì)胞的端粒長度。相對(duì)于健康人及跟蹤期內(nèi)血清tba無升高或者僅一過性升高的chb患者,跟蹤期內(nèi)血清tba持續(xù)升高的chb患者其naivet細(xì)胞的端粒長度顯著縮短,縮短到了與hbv相關(guān)的hcc患者類似的水平。我們這部分的研究表明chb患者的t細(xì)胞免疫衰老與chb患者血清tba持續(xù)升高有緊密的相關(guān)性,很可能由血清tba持續(xù)升高的chb患者其外周t細(xì)胞長期保持異�；罨鲋硨�(dǎo)致。為了研究血清tba持續(xù)升高對(duì)于chb患者發(fā)生hcc的影響,我們做了一個(gè)回顧性的觀察性的隊(duì)列研究。回顧性研究的數(shù)據(jù)來源于hbs(hepatitisbiobankatsouthwesthospital,西南醫(yī)院肝炎樣本庫)項(xiàng)目2001年至2014年的數(shù)據(jù),該樣本庫包含了到西南醫(yī)院傳染科就診的患者其人口統(tǒng)計(jì)學(xué)方面及臨床指標(biāo)方面的一系列記錄。按照我們的篩選標(biāo)準(zhǔn),一共有3021位chb患者進(jìn)入最終隊(duì)列,其中3018(99.%)位在跟蹤期間都有定期的通過干擾素或者核苷類似物的抗病毒治療。我們利用coxproportionalhazardmodels、kaplan-meieranalyses、以及propensityscoreanalyses來分析血清TBA持續(xù)升高與CHB患者發(fā)生HCC的相關(guān)性。我們的分析選擇了性別、年齡、肝硬化、血清ALT(Alanine Aminotransferase,丙氨酸氨基轉(zhuǎn)移酶)、血清HBV DNA、以及血清HBe Ag(Hepatitis B e Antigen,乙型肝炎e抗原)這幾個(gè)公認(rèn)的CHB患者HCC發(fā)生的危險(xiǎn)因素與血清TBA一起作為協(xié)變量(covariate)。CHB患者跟蹤期間血清TBA升高的持續(xù)程度由其血清TBA升高的跟蹤時(shí)間占其總跟蹤時(shí)間的比值決定。根據(jù)這個(gè)比值,我們把CHB患者其跟蹤期間血清TBA長期變化模式按照升高的持續(xù)程度分為3群:血清TBA無升高或一過性升高、血清TBA中等水平的持續(xù)升高、血清TBA高水平的持續(xù)升高�；仡櫺匝芯靠偢櫰跒�20,813.7 person-years,一共有81例CHB患者跟蹤期內(nèi)發(fā)生了HCC。在3021例隊(duì)列CHB患者中,血清TBA無升高或一過性升高的CHB患者為2139(70.8%)例,血清TBA中等水平的持續(xù)升高的CHB患者為520(17.2%)例,血清TBA高水平的持續(xù)升高的CHB患者為362(12.0%)例。整個(gè)跟蹤期內(nèi),血清TBA長期變化模式為無升高或一過性升高、中等水平的持續(xù)升高、及高水平的持續(xù)升高的CHB患者其HCC累積發(fā)病率分別為2.2%、6.3%、及19.3%。相對(duì)于血清TBA長期變化模式為無升高或一過性升高的CHB患者,血清TBA長期變化模式為中等水平的持續(xù)升高、及高水平的持續(xù)升高的CHB患者其多因素校正(multivariate adjusted)之后的HRs(Hazard Ratios,風(fēng)險(xiǎn)比)及95%CI(Confidence Interval,置信區(qū)間)分別為1.70(0.88-3.26)、及3.08(1.69-5.60)�；谠揌Rs值計(jì)算出來血清TBA長期變化模式為中等水平的持續(xù)升高、及高水平的持續(xù)升高對(duì)于HCC發(fā)生的PARs(Population Attributable Risks,人群歸因危險(xiǎn)度)分別為7.8%、及29.0%�；趐ropensity score models的分析也驗(yàn)證了CHB患者其跟蹤期間血清TBA升高的持續(xù)程度與HCC發(fā)生的這種劑量-反應(yīng)關(guān)系(Dose-response Relationship)。我們這部分的研究表明,血清TBA的持續(xù)升高是定期接受抗病毒治療的CHB患者人群發(fā)生HCC的主要的、獨(dú)立的風(fēng)險(xiǎn)因素。綜上所述,我們的研究表明血清TBA的持續(xù)升高的CHB患者其HCC發(fā)生的風(fēng)險(xiǎn)升高,這群CHB患者升高的HCC風(fēng)險(xiǎn)很可能是由其T細(xì)胞免疫衰老導(dǎo)致。實(shí)際臨床應(yīng)用上,我們的發(fā)現(xiàn)表明對(duì)血清TBA水平的持續(xù)升高的CHB患者執(zhí)行定期的HCC篩查能夠保證在該HCC高風(fēng)險(xiǎn)患者群體及時(shí)地發(fā)現(xiàn)早期HCC,有利于后期的治療。理論層面上,我們的發(fā)現(xiàn)對(duì)于從免疫學(xué)的角度來理解HCC的發(fā)生提供了一個(gè)很好的切入點(diǎn)。
[Abstract]:With the increase of age, innate and acquired immune system functional degradation, resulting in decreased immunity, this phenomenon is often called immunosenescence. Immunosenescence is usually considered with the elderly on immune responses to vaccines reduced, prone to viral or bacterial infection, prone to cancer. As a major component of gain of the immune system, T cell immune function degradation during senescence is concerned.T cell immune senescence most often phenotypes of degenerative changes, multiple levels of T cell immune system including: the number of naive T cells decreased, TCR (T-cell Receptor, T cell receptor) repertoire diversity decreased telomere T cell shortening, function of memory T cells decreased. The results of the present study showed that chronic infection has a negative impact on the immune system. In this study, we analyzed is No CHB (Chronic Hepatitis B, chronic hepatitis B) in patients with impaired T cell immune system at the same time, we also analyzed whether CHB T cells in patients with impaired immune systems and HCC (Hepatocellular Carcinoma, HCC). We compared 24 patients with CHB and 15 healthy people in the naive T Library of TCR cells repertoire. reported results consistent with previous studies, 40 healthy people before the age of the naive T cell library TCR repertoire diversity did not significantly decrease remained at a high level. Different from healthy people, patients aged 40 years before CHB naive T cell library TCR repertoire diversity increased with age significantly reduced. Considering the 24 cases of CHB patients are infected by vertical transmission of HBV (Hepatitis B Virus, hepatitis B virus), we believe that to reduce the naive T cell library TCR repertoire diversity is due to the HBV virus and T cell immune system The result of long-term effect and not by age increases. Like healthy human naive T cell library, T cell clones did not express specific TCR clone type occupies the dominant position in the naive T cell library, which indicates that CHB patients with naive T TCR repertoire cell library diversity reduction was not caused by T cells the advantages of cloning some specific TCR amplification and cloning of the type, is likely to reflect the loss of CHB in the naive of patients with T cell T cell clone library uniformity. We found this part of the study showed that chronic CHB infection can accelerate T cell immunity in patients with CHB.Naive T cells senescence library TCR repertoire diversity reduction means maintain the imbalance of T cell library CHB patients. Adult peripheral T cells maintain the library mainly through the slow proliferation of T cells to achieve. Firstly, we analyzed 146 cases of CHB patients and 53 cases of healthy human peripheral T cells The proliferation of CHB. Compared with healthy people, patients with peripheral T cell proliferation was significantly increased. CHB patients with peripheral T cell proliferation level was increased to HIV-1 (humanimmunodeficiencyvirustype1, human immunodeficiency virus type 1 infection) level of serum.Chb in patients with TBA (total bile acid totalbildacid) and elevated levels of peripheral T cells the proliferation was significantly related, which is mainly reflected in: analysis from the qualitative point of view, the level of serum TBA in CHB patients with all its subsets of T cells (including naivet cells and memoryt cells) proliferation frequency with serum TBA in CHB patients and normal healthy people was significantly increased; the analysis from the quantitative point of view is significantly related to serum TBA increased in CHB patients with peripheral T cell proliferation frequency and serum TBA. We also analyzed the correlation between increased in patients with CHB peripheral T cell proliferation level and other clinical indicators related to CHB, There was no significant correlation between similar findings. Then, we analyzed the proliferation level of T cells in 11 cases of CHB patients with persistently elevated serum level of TBA in two different time points, and it is found that the T cells maintain a high level of proliferation at two time points before and after. This showed that the serum TBA elevated CHB patients, peripheral T cells it may keep in excessive proliferation. Further, we analyzed the activation of 12 cases of elevated serum TBA CHB in patients with peripheral T cells, and compare the distribution of T cells and the rest 12 cases of CHB patients and 3 healthy people and Zhou Zengzhi's T cell TCRV beta family. The expression of serum TBA increased the proliferation of T cells in CHB patients showed upregulation of CD38, the proliferation of immune activation. Although there is a huge difference, the distribution of TCRV beta family T cells and resting CHB patients and healthy human serum TBA elevated the proliferation of T cells are highly similar This shows that the bypass. Antigen nonspecific activation (by-standeractivation) mechanism dominates the increase of serum TBA in patients with CHB elevated peripheral T cell proliferation level. Finally, we analyzed 5 cases of healthy people, 21 cases of more than 4 years follow-up of CHB patients, the telomere length in 4 cases of HBV associated HCC in naivet cells compared to healthy people. And the tracking period of serum TBA increased no or only a transient increase in CHB patients, the tracking period of persistently elevated serum level of TBA CHB in naivet cells significantly shortened telomere length, reduced to a similar HBV related with HCC level. This part of our study showed that patients with CHB t cellular senescence and CHB in serum of patients with persistently elevated TBA is associated with CHB in peripheral T cells, possibly by increasing serum TBA long-term abnormal activation and proliferation cause. In order to study the serum TBA increased The effect of CHB in patients with HCC, we conducted a retrospective observational cohort study. A retrospective study of data from the HBS (hepatitisbiobankatsouthwesthospital, Southwest Hospital Sample Library) project in 2001 to 2014 data, the sample library contains a set of records to the Southwest Hospital Department of infectious disease patients and its demographics clinical indicators. According to our selection criteria, a total of 3021 patients with CHB into the final queue, of which 3018 (99%) in the tracking period regularly through antiviral therapy of interferon or nucleoside analogs. We use coxproportionalhazardmodels, kaplan-meieranalyses, and propensityscoreanalyses to analyze the relationship between the serum levels of TBA increased in patients with CHB HCC the analysis. We chose the gender, age, liver cirrhosis, serum ALT (Alanine Aminot Ransferase, alanine aminotransferase), serum HBV DNA, serum HBe and Ag (Hepatitis B e Antigen, hepatitis B e antigen) the risk factors of several recognized CHB HCC patients with serum TBA as covariates (covariate) patients with.CHB ratio during continuous tracking of the level of serum TBA by the serum TBA the tracking time of the total time tracking decision. According to this ratio, we put the CHB in tracking mode according to long-term changes in serum TBA during sustained elevated levels of serum TBA were divided into 3 groups: no increase or a transient increase in serum TBA, medium level continues to rise, high serum levels of TBA were rising. Study on the total follow-up period was 20813.7 person-years, a total of 81 cases of CHB patients with follow-up period occurred in 3021 cases of HCC. queue in CHB patients, serum TBA increased or a transient increase in CHB patients was 2139 (70.8%) Patients, serum TBA level increased in moderate CHB patients was 520 (17.2% cases), high serum levels of TBA increased in CHB patients was 362 (12%) cases. The follow-up period, serum TBA long-term variation pattern with no increase or a transient increase, the medium level continues to rise, and a high level the rising of CHB patients the cumulative incidence of HCC were 2.2%, 6.3%, and 19.3%. relative to the long-term changes in serum TBA pattern with no increase or a transient increase in CHB patients, serum TBA increased for long-term changes in mode of moderate levels of correction and high level increased in CHB patients (multi factor multivariate adjusted HRs (Hazard) after Ratios, the risk ratio) and 95%CI (Confidence Interval CI) were 1.70 (0.88-3.26), and 3.08 (1.69-5.60). The HRs value calculated from the increasing serum TBA of long term changes for intermediate level based on model, The high level and continues to rise for the occurrence of HCC PARs (Population Attributable Risks, the population attributable risk was 7.8%), and 29.0%. analysis of propensity score based on models also verified the relationship between patients with CHB and HCC during the tracking duration of elevated serum TBA occurred in this kind of dose response (Dose-response Relationship) that we. Some studies show that serum TBA increased regularly receive antiviral treatment of patients with CHB who have HCC the main independent risk factors. In summary, our study showed that the increased risk of sustained high level of serum TBA in CHB patients HCC, this group of patients with CHB increased the risk of HCC is likely to be caused by the T cell immunosenescence. Clinical application, we found that the level of serum TBA increased in patients with CHB HCC to ensure the regular screening The HCC high-risk group can find early HCC in time, which is conducive to the later treatment. In theory, our findings provide a good breakthrough point for understanding the occurrence of HCC from the perspective of immunology.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R735.7;R512.62

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9 王寧玲 ,戴海明 ,劉芝璋 ,翟志敏;特發(fā)性血小板減少性紫癜患兒T細(xì)胞免疫功能研究[J];臨床兒科雜志;2003年09期

10 周平,呂楓林,姚詠明,王江,于燕;特發(fā)性血小板減少性紫癜患兒T細(xì)胞免疫功能的變化[J];中華兒科雜志;1999年01期

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